Affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.

ABSTRACTThe study of HIV-infected "controllers" who are able to maintain low levels of plasma HIV RNA in the absence of antiretroviral therapy (ART) may provide insights for HIV cure and vaccine strategies. Despite maintaining very low levels of plasma viremia, controllers have elevated immune activation and accelerated atherosclerosis. However, the degree to which low-level replication contributes to these phenomena is not known. Sixteen asymptomatic controllers were prospectively treated with ART for 24 weeks. Controllers had a statistically significant decrease in ultrasensitive plasma and rectal HIV RNA levels with ART. Markers of T cell activation/dysfunction in blood and gut mucosa also decreased substantially with ART. Similar reductions were observed in the subset of "elite" controllers with pre-ART plasma HIV RNA levels below conventional assays (<40 copies/mL). These data confirm that HIV replication persists in controllers and contributes to a chronic inflammatory state. ART should be considered for these individuals (ClinicalTrials.gov NCT01025427).

ppat-1003691-g003: Change in cell-associated HIV RNA and total HIV DNA in rectum.Thin lines indicate data for each individual subject. The thick line indicates the estimated mean value over time from mixed effects linear regression. P-values refer to change from baseline at each referenced time-point.

Mentions:
At baseline, the median (IQR) levels of cell-associated HIV RNA and total HIV DNA in PBMCs were 6.9 (3.5, 45.7) S/Co per million CD4+ T cells and 57 (34, 138) copies/million CD4+ T cells, respectively. In PBMCs, controllers did not have a substantial decrease in cell-associated HIV RNA (mean 1.20-fold decrease in S/Co per million CD4+ T cells, 95% CI 2.4-fold decrease to 1.62-fold increase, p = 0.58) or total HIV DNA (mean 1.22-fold decrease in copies/million CD4+ T cells, 95% CI 1.95-fold decrease to 1.32-fold increase, p = 0.41) at week 24. However, controllers did have an early and persistent decrease in rectal cell-associated HIV RNA after initiation of ART, with a mean decrease of 0.61 log10 copies/million CD4+ cells, which corresponded to a 4.1-fold decrease (95% CI 12.0 to 1.40-fold decrease, p = 0.010) at week 22 (Fig. 3A). There was a similar trend towards a decrease in rectal total HIV DNA, with a mean decrease of 0.28 log10 copies/million CD4+ cells, which corresponded to a 1.91-fold decrease (95% CI 5.1-fold decrease to 1.38-fold increase, p = 0.19) at week 22 (Fig. 3B). We also measured integrated HIV DNA levels in PBMCs obtained through leukapheresis in 5 controllers. In these subjects, there was a statistically significant decrease in integrated HIV DNA after initiation of ART, with a mean decrease of 0.32 log10 copies/million PBMCs, which corresponded to a 2.1-fold decrease (95% CI 2.7 to 1.13-fold decrease, p = 0.027) at week 21 (Fig. 4).

ppat-1003691-g003: Change in cell-associated HIV RNA and total HIV DNA in rectum.Thin lines indicate data for each individual subject. The thick line indicates the estimated mean value over time from mixed effects linear regression. P-values refer to change from baseline at each referenced time-point.

Mentions:
At baseline, the median (IQR) levels of cell-associated HIV RNA and total HIV DNA in PBMCs were 6.9 (3.5, 45.7) S/Co per million CD4+ T cells and 57 (34, 138) copies/million CD4+ T cells, respectively. In PBMCs, controllers did not have a substantial decrease in cell-associated HIV RNA (mean 1.20-fold decrease in S/Co per million CD4+ T cells, 95% CI 2.4-fold decrease to 1.62-fold increase, p = 0.58) or total HIV DNA (mean 1.22-fold decrease in copies/million CD4+ T cells, 95% CI 1.95-fold decrease to 1.32-fold increase, p = 0.41) at week 24. However, controllers did have an early and persistent decrease in rectal cell-associated HIV RNA after initiation of ART, with a mean decrease of 0.61 log10 copies/million CD4+ cells, which corresponded to a 4.1-fold decrease (95% CI 12.0 to 1.40-fold decrease, p = 0.010) at week 22 (Fig. 3A). There was a similar trend towards a decrease in rectal total HIV DNA, with a mean decrease of 0.28 log10 copies/million CD4+ cells, which corresponded to a 1.91-fold decrease (95% CI 5.1-fold decrease to 1.38-fold increase, p = 0.19) at week 22 (Fig. 3B). We also measured integrated HIV DNA levels in PBMCs obtained through leukapheresis in 5 controllers. In these subjects, there was a statistically significant decrease in integrated HIV DNA after initiation of ART, with a mean decrease of 0.32 log10 copies/million PBMCs, which corresponded to a 2.1-fold decrease (95% CI 2.7 to 1.13-fold decrease, p = 0.027) at week 21 (Fig. 4).

Affiliation:
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.

ABSTRACTThe study of HIV-infected "controllers" who are able to maintain low levels of plasma HIV RNA in the absence of antiretroviral therapy (ART) may provide insights for HIV cure and vaccine strategies. Despite maintaining very low levels of plasma viremia, controllers have elevated immune activation and accelerated atherosclerosis. However, the degree to which low-level replication contributes to these phenomena is not known. Sixteen asymptomatic controllers were prospectively treated with ART for 24 weeks. Controllers had a statistically significant decrease in ultrasensitive plasma and rectal HIV RNA levels with ART. Markers of T cell activation/dysfunction in blood and gut mucosa also decreased substantially with ART. Similar reductions were observed in the subset of "elite" controllers with pre-ART plasma HIV RNA levels below conventional assays (<40 copies/mL). These data confirm that HIV replication persists in controllers and contributes to a chronic inflammatory state. ART should be considered for these individuals (ClinicalTrials.gov NCT01025427).